When dealing with potentially curative diseases, the stakes are high. Thus, it is important to carefully weigh the risks and benefits of phase II results and give patients the benefit of the doubt when survival may be improved.

—Wyndham H. Wilson, MD, PhD

Joseph M. Connors, MD, authored a commentary in the June 25 issue of The ASCO Post inspired by a recent New England Journal of Medicine publication on dose-adjusted EPOCH-R chemotherapy (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) for primary mediastinal B-cell lymphoma. He summarized his reaction to the study as “It’s déjà vu all over again,” in reference to the pivotal Southwest Oncology Group (SWOG)-8516 trial, which compared CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) to the third-generation regimens—and which celebrated its 20-year anniversary on the publication date of the dose-adjusted EPOCH-R study.1

Cautionary Tale

For 20 years, SWOG-8516 has been heralded as the cautionary tale against clinically implementing results of phase II clinical trials in newly diagnosed diffuse large B-cell lymphoma. Dr. Connors reminds us that “In the 1980s, several groups … reported remarkably better outcomes for patients with diffuse large cell lymphoma when they were treated with ProMACE-CytaBOM (cyclophosphamide, doxorubicin, etoposide, cytarabine, bleomycin, vincristine, methotrexate, and prednisone), m-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone), or MACOP-B (methotrexate, doxorubicin, cyclohosphamide, vincristine, prednisone, and bleomycin” compared to CHOP.

He goes on to note that history (by way of SWOG-8516) proved them all wrong. This tale of misguided hope has been a battle cry by some against clinically embracing phase II results, while others have promoted inadequately tested ideas from arms of phase III trials, such as R-CHOP-14 in untreated diffuse large B-cell lymphoma.2

As in all matters, and especially in science, the devil is in the details. So let’s take a look at the landscape of the SWOG-8516 randomized study. The era was hampered by two significant issues: (1) the absence of a validated prognostic score to compare patients across trials, and (2) a crude understanding of histopathology as manifested by the Working Formulation.3 Both of these issues played roles in the perceived improvement in third-generation treatments during the 1980s.

Nuanced Picture

A critical look paints a nuanced picture for the superiority of third-generation regimens at the time. In 1984, Armitage et al published a study of CHOP in diffuse histiocytic lymphoma—for our younger colleagues, diffuse histiocytic lymphoma is the historical term for diffuse large B-cell lymphoma—that showed an (estimated) freedom from progression of 41.5% at approximately 3 years, setting a benchmark for CHOP.4

In 1991, Longo et al published an important randomized study of ProMACE-MOPP (prednisone, methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, etoposide, mechlorethamine, vincristine, procarbazine) vs ProMACE-CytaBOM that showed an (estimated) freedom from progression of 63% at 5-years for ProMACE-CytaBOM.5 Like the other single-institution studies of m-BACOD and MACOP-B, this result suggested a major advance in the cure of diffuse large B-cell lymphoma, or a “home run,” as Dr. Connors felt at the time.

What appears to have been forgotten is that SWOG performed a series of phase II trials of ProMACE-CytaBOM (SWOG-8503), m-BACOD (SWOG-8410) and MACOP-B (SWOG-8508) as a prelude to the SWOG-8516 randomized study and reported 3-year failure-free survivals of approximately 37%, 35%, and 42%, respectively—all no different from CHOP!6-8 Thus, it came as little surprise that all of these regimens performed similarly in the SWOG randomized study, reported in 1993, where the treatment failure rates were 41% (CHOP), 46% (ProMACE-CytaBOM), 46% (m-BACOD), and 41% (MACOP-B) at 3 years.1

Historical Ironies

What lessons should we take from SWOG-8516? Certainly not that all phase II trials are suspect. Indeed, the SWOG multicenter trials recapitulated the phase III results. While the single-institution trials suffered from patient selection bias, which appears to mostly account for the favorable results, this pitfall has been largely overcome by the International Prognostic Index (IPI). Perhaps the most important lesson is that the results of the SWOG multicenter phase II trials should have been heeded.

Dr. Connors wisely quotes George Santayana: “Those who cannot remember the past are condemned to repeat it.” When we began the development of EPOCH in 1989, we endeavored to remember history. We performed multiple studies of dose-adjusted EPOCH with and without rituximab and showed consistently better results compared to multiple studies of CHOP with and without rituximab when analyzed by IPI risk groups and histology.9-12

These studies eventually led to two multicenter phase II studies of dose-adjusted EPOCH-R performed by the Cancer and Leukemia Group B ­(CALGB) and AIDS Malignancies Consortium (AMC) cooperative groups that validated our results.13,14 Dose-adjusted EPOCH-R for primary mediastinal B-cell lymphoma followed a similar development path, with the patients having comparable prognostic characteristics to the patients in the studies of R-CHOP (which include radiation) for the same disease, and confirmation in an independent validation cohort.

It is also important to consider the role of tumor biology in the conduct of clinical trials for diffuse large B-cell lymphoma. Unfortunately, most trials remain agnostic to the molecular subtypes of diffuse large B-cell lymphoma (germinal center B-cell, activated B-cell, and primary mediastinal B-cell), which are as different from one another as they are from Hodgkin and Burkitt lymphomas.15,16

The irony of this should not be lost on primary mediastinal B-cell lymphoma aficionados, who know that regimens like MACOP-B plus radiation may be a better platform than CHOP plus radiation.17 To add further irony, R-CHOP (with or without radiation) has never been prospectively studied in primary mediastinal B-cell lymphoma and yet is considered by many to be the de facto standard.

Clinical Implementation

How should we clinically implement promising results of phase II trials in oncology? The Food and Drug Administration weighs the issue of risk-benefit for accelerated drug approval, which is typically based on ­single-arm phase II trials. The burden of proof is based on regulatory language that a drug is “reasonably likely to provide clinical benefit” and has a favorable risk profile.

When dealing with potentially curative diseases, the stakes are high. Thus, it is important to carefully weigh the risks and benefits of phase II results and give patients the benefit of the doubt when survival may be improved. ■